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Protein-transport discoveries may someday help those with AIDS, cancers

Sep 29, 2010

By Amanda Siegfried / September 2010

Millions of times each day, thousands of proteins that regulate biological processes within a cell must be transported into and out of the cell’s nucleus. The volume and complexity of the traffic flow makes Dallas rush hour look like a drive in the country.

Dr. Yuh Min Chook, associate professor of pharmacology, investigates how proteins are imported and exported from the cell nucleus, and her work is shedding light on fundamental aspects of cell biology.

But the research also might hold the key to developing new treatment approaches to such diseases as HIV/AIDS and cancer — in particular acute myeloid leukemia, or AML, a devastating disease that is difficult to treat. In these illnesses and others, the import/export mechanism of proteins through pores in the cells’ nuclear membrane goes awry.

Dr. Yuh Min Chook (left) and postdoctoral researcher Dr. Xiuhua Dong have won recent awards that will allow them to pursue disease-oriented research.

In recognition of those potential medical applications, Dr. Chook and a postdoctoral researcher in her laboratory, Dr. Xiuhua Dong, recently garnered two awards that will allow them to pursue further their disease-oriented research.

Dr. Chook is the recipient of a 2010 Leukemia & Lymphoma Society Scholar Award, which began July 1 and includes $110,000 a year for five years.

In January, Dr. Dong received a Mathilde Krim Fellowship in Basic Biomedical Research from amfAR, The Foundation for AIDS Research, which will fund her research for up to three years. The fellowship supports early-career investigators examining how HIV interacts with host cells.

“It’s gratifying that medical experts with disease-focused organizations recognize our work and have confidence that we really could make a difference,” Dr. Chook said.

Nobel Prize-inspired work

In two related studies published last year in Nature and Nature Structural & Molecular Biology, Dr. Dong, Dr. Chook and colleagues described for the first time the 3-D structure of one of the proteins responsible for trucking other proteins out of the nucleus. The transport molecule, called CRM1 (“CREM-one”), belongs to a family of proteins known as kap-betas. CRM1 ferries about 300 “cargo” proteins out of the cell nucleus.

While many of the proteins CRM1 transports are related to normal functions, some are linked to disease, including BRCA1 and BRCA2, which play a role in breast cancer; the tumor-suppressor protein p53; and an HIV protein called REV.

“It’s very tricky to work with CRM1 because you could only make small amounts of it, and it doesn’t behave well. Many researchers worked on it for many years, and some gave up,” Dr. Chook said. “But Xiuhua was very determined, and she was able to increase production of it, and make it pure and active. She tamed the beast.”

In addition, the researchers have determined the structure of the “docking point” on a cargo protein to which CRM1 binds.

This docking point, also called a nuclear export signal, is a specific protruding structure with-in the cargo protein that signals CRM1 to attach and transport the protein out of the nucleus.

Dr. Chook’s dissertation adviser, Dr. Günter Blobel of The Rockefeller University, won the 1999 Nobel Prize in physiology or medicine for his discovery that proteins have such intrinsic signals that govern their transport within the cell, but the UT Southwestern researchers are the first to deter­mine the detailed molecular structure of such an export signal.

Cell’s mass-transit system

Dr. Chook likens the dynamic relationship between kap-beta proteins such as CRM1 and their cargo to a busy bus line.

“Imagine that the pore through the nuclear membrane is the Lincoln Tunnel, connecting Manhattan and New Jersey,” Dr. Chook explained, “and there are only special buses that are allowed to go through the tunnel. These are the kap-betas. They carry within them distinct sets of passengers or cargoes, which are the proteins that they transport.”

Each passenger is allowed on its bus because each carries a specific export signal — like a bus pass — that is recognized only by that particular vehicle.

“If passengers don’t have the correct bus pass, they can’t get on the bus, and they’re stuck in Jersey — or in this case, the cell nucleus,” Dr. Chook said. “We think that many proteins CRM1 transports probably contain a similarly structured nuclear export signal.”

Because proteins related to both normal functions and disease use the CRM1 transport system, potential drugs that treat disease by interfering with CRM1 binding could be problematic, Dr. Chook said. While that presents challenges, she said, her lab is prepared to take them on.

Implications for HIV/AIDS

For example, Dr. Dong is investigating how CRM1 transports the HIV protein REV out of the nucleus. When HIV infects a cell, it releases its genetic material — ribonucleic acid (RNA) — into the cell’s nucleus, which replicates more copies of the viral RNA. The REV protein gathers up this RNA, then binds to CRM1 for its trip out of the nucleus. Once loose, the viral material infects other cells.

Dr. Dong’s work suggests that CRM1 binds to REV not only through the nuclear export signal common to other cargo proteins, but also to additional sites that are specific to REV. She said these sites might be targets for drugs that could block the REV nuclear transport process without interfering with CRM1’s transport of normal proteins.

“This is an important field and a hot area of research,” Dr. Dong said. “Our work has now taken a completely different direction. It’s very exciting.”

Moving bench science to bedside

In the case of acute myeloid leukemia, which Dr. Chook is studying, a genetic mutation causes a certain protein residing in the cell nucleus to be malformed. Normally this protein does not have an export signal and remains in the nucleus. The mutation, however, creates a modified protein that contains a nuclear export signal, allowing it to hitch a ride on CRM1 out of the nucleus, where it contributes to uncontrolled cell growth and other processes leading to leukemia.

“This protein is supposed to be in the nucleus; now it’s out. We are trying to understand this new gain-of-function export signal,” Dr. Chook said. “If we can get a handle on how it’s recognized by CRM1, maybe we can figure out how to stop it.”

Dr. Chook also has begun to collaborate with a biopharmaceutical company that focuses on developing drugs that target the nuclear transport system in order to treat cancer, inflammation and viral infection.

Dr. Chook’s research is supported in part by the National Institutes of Health and The Welch Foundation, as well as by a 2007 grant she received through UT Southwestern’s High Impact/High Risk Research Program, which allows faculty members to explore novel hypotheses and con­duct research that could have enormous impact, even though there is a substantial risk of failure.